The mechanism of viral persistence remains a major unresolved problem in virology. The long-term goal of these studies is to understand the mechanisms by which virus evade or suppress the immune response and persist in the host. Persistent viral infections are medically significant because they often have severe consequences in immunosuppressed individuals, and have also been associated with neoplasms and immunopathological diseases. Infection of mice with lymphocytic choriomeningitis virus (LCMV) provides an excellent model for studying the interaction between the virus and the immune system of it's natural host, and in defining conditions that lead to viral clearance or persistence. The objectives of the proposed research are three-fold. First, to analyze the genetic differences between wild type LCMV and LCMV variants, and to map the viral genes that allow the variants to suppress cytotoxic T cell (CTL) responses and cause persistent infections in adult immunocompetent mice. Second, to determine the role of host organs and cell types in selection of unique organ specific virus variants. Third, to examine the interaction of the variants with T cells and macrophages to elucidate the mechanism of CTL suppression. These studies, combining the disciplines of virology and immunology, should provide insight into the genetic basis of viral persistence.